Cortical neuronal and glial pathology in TgTauP301L transgenic mice

Neuronal degeneration, memory disturbance, and phenotypic variation

Tetsuro Murakami, Erwan Paitel, Takeshi Kawarabayashi, Masaki Ikeda, M. Azhar Chishti, Christopher Janus, Etsuro Matsubara, Atsushi Sasaki, Toshitaka Kawarai, Amie L. Phinney, Yasuo Harigaya, Patrick Horne, Nobuaki Egashira, Kenichi Mishima, Amanda Hanna, Jing Yang, Katsunori Iwasaki, Mitsuo Takahashi, Michihiro Fujiwara, Koichi Ishiguro & 6 others Catherine Bergeron, George A. Carlson, Koji Abe, David Westaway, Peter St. George-Hyslop, Mikio Shoji

Research output: Contribution to journalArticle

42 Citations (Scopus)

Abstract

Recapitulation of tau pathologies in an animal model has been a long-standing goal in neurodegenerative disease research. We generated transgenic (TgTauP301L) mice expressing a frontotemporal dementia with parkinsonism linked to chromosome 17 (FTPD-17) mutation within the longest form of tau (2N, 4R). TgTauP301L mice developed florid pathology including neuronal pretangles, numerous Gallyas-Braak-positive neurofibrillary tangles, and glial fibrillary tangles in the frontotemporal areas of the cerebrum, in the brainstem, and to a lesser extent in the spinal cord. These features were accompanied by gliosis, neuronal loss, and cerebral atrophy. Accumulated tau was hyperphosphorylated, conformationally changed, ubiquitinated, and sarkosyl-insoluble, with electron microscopy demonstrating wavy filaments. Aged TgTauP301L mice exhibited impairment in hippocampally dependent and independent behavioral paradigms, with impairments closely related to the presence of tau pathologies and levels of insoluble tau protein. We conclude that TgTauP301L mice recreate the substantial phenotypic variation and spectrum of pathologies seen in FTDP-17 patients. Identification of genetic and/or environmental factors modifying the tau phenotype in these mice may shed light on factors modulating human tauopathies. These transgenic mice may aid therapeutic development for FTDP-17 and other diseases featuring accumulations of four-repeat tau, such as Alzheimer's disease, corticobasal degeneration, and progressive supranuclear palsy.

Original languageEnglish
Pages (from-to)1365-1375
Number of pages11
JournalAmerican Journal of Pathology
Volume169
Issue number4
DOIs
Publication statusPublished - Oct 2006

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Neuroglia
Frontotemporal Dementia
Transgenic Mice
Pathology
Tauopathies
Progressive Supranuclear Palsy
tau Proteins
Chromosomes, Human, Pair 17
Neurofibrillary Tangles
Gliosis
Cerebrum
Neurodegenerative Diseases
Brain Stem
Atrophy
Spinal Cord
Electron Microscopy
Alzheimer Disease
Animal Models
Phenotype
Mutation

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Cortical neuronal and glial pathology in TgTauP301L transgenic mice : Neuronal degeneration, memory disturbance, and phenotypic variation. / Murakami, Tetsuro; Paitel, Erwan; Kawarabayashi, Takeshi; Ikeda, Masaki; Chishti, M. Azhar; Janus, Christopher; Matsubara, Etsuro; Sasaki, Atsushi; Kawarai, Toshitaka; Phinney, Amie L.; Harigaya, Yasuo; Horne, Patrick; Egashira, Nobuaki; Mishima, Kenichi; Hanna, Amanda; Yang, Jing; Iwasaki, Katsunori; Takahashi, Mitsuo; Fujiwara, Michihiro; Ishiguro, Koichi; Bergeron, Catherine; Carlson, George A.; Abe, Koji; Westaway, David; St. George-Hyslop, Peter; Shoji, Mikio.

In: American Journal of Pathology, Vol. 169, No. 4, 10.2006, p. 1365-1375.

Research output: Contribution to journalArticle

Murakami, T, Paitel, E, Kawarabayashi, T, Ikeda, M, Chishti, MA, Janus, C, Matsubara, E, Sasaki, A, Kawarai, T, Phinney, AL, Harigaya, Y, Horne, P, Egashira, N, Mishima, K, Hanna, A, Yang, J, Iwasaki, K, Takahashi, M, Fujiwara, M, Ishiguro, K, Bergeron, C, Carlson, GA, Abe, K, Westaway, D, St. George-Hyslop, P & Shoji, M 2006, 'Cortical neuronal and glial pathology in TgTauP301L transgenic mice: Neuronal degeneration, memory disturbance, and phenotypic variation', American Journal of Pathology, vol. 169, no. 4, pp. 1365-1375. https://doi.org/10.2353/ajpath.2006.051250
Murakami, Tetsuro ; Paitel, Erwan ; Kawarabayashi, Takeshi ; Ikeda, Masaki ; Chishti, M. Azhar ; Janus, Christopher ; Matsubara, Etsuro ; Sasaki, Atsushi ; Kawarai, Toshitaka ; Phinney, Amie L. ; Harigaya, Yasuo ; Horne, Patrick ; Egashira, Nobuaki ; Mishima, Kenichi ; Hanna, Amanda ; Yang, Jing ; Iwasaki, Katsunori ; Takahashi, Mitsuo ; Fujiwara, Michihiro ; Ishiguro, Koichi ; Bergeron, Catherine ; Carlson, George A. ; Abe, Koji ; Westaway, David ; St. George-Hyslop, Peter ; Shoji, Mikio. / Cortical neuronal and glial pathology in TgTauP301L transgenic mice : Neuronal degeneration, memory disturbance, and phenotypic variation. In: American Journal of Pathology. 2006 ; Vol. 169, No. 4. pp. 1365-1375.
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AU - Kawarabayashi, Takeshi

AU - Ikeda, Masaki

AU - Chishti, M. Azhar

AU - Janus, Christopher

AU - Matsubara, Etsuro

AU - Sasaki, Atsushi

AU - Kawarai, Toshitaka

AU - Phinney, Amie L.

AU - Harigaya, Yasuo

AU - Horne, Patrick

AU - Egashira, Nobuaki

AU - Mishima, Kenichi

AU - Hanna, Amanda

AU - Yang, Jing

AU - Iwasaki, Katsunori

AU - Takahashi, Mitsuo

AU - Fujiwara, Michihiro

AU - Ishiguro, Koichi

AU - Bergeron, Catherine

AU - Carlson, George A.

AU - Abe, Koji

AU - Westaway, David

AU - St. George-Hyslop, Peter

AU - Shoji, Mikio

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